ABSTRACT The recently proposed Ending the HIV Epidemic (EHE) Initiative includes four pillars: Diagnose, Treat, Protect, and Respond. Research that involves the ?Respond? pillar of the EHE Initiative may be associated with barriers not observed with the other three EHE pillars, due to a set of associated scientific, ethical, legal and social challenges. The success of EHE research applications will be contingent upon carefully addressing the implementation challenges of this prevention strategy. This proposal will take the innovative leap of addressing the Ethical, Legal and Social Implications (ELSI) of an array of potential ME-informed HIV prevention efforts developed by simulations, parameterized using real-world data, and incorporating current and emerging technological and analytic approaches. These quantitative estimates will inform our efforts to understand the ethical, legal, and social issues related to ME, as well as guide policy development to attenuate concerns related to them. The proposed study, ?Perspectives Among Key Populations of the Risks and Benefits of Molecular Epidemiology for HIV Prevention (HIV-ME)? will engage a national population of persons living with HIV (PLWH) and persons at risk without HIV (PWoH) in a multi-method examination of the ELSI of ME-informed inferences (i.e., identification of individuals with genetically linked HIV sequences) to facilitate successful implementation of ME-guided HIV prevention research. Key populations, including men who have sex with men, transgender women, and persons who inject drugs in geographic areas prioritized by the EHE initiative will be included. Quantitative and qualitative methods will be informed by well-characterized estimates of benefit (e.g., improved risk stratification by molecular surveillance) and risk (e.g., inferred directionality of transmission and false identification) derived from simulations of a well characterized U.S. HIV epidemic. To date, there has not been a comprehensive effort to provide quantitative estimates of the actual risks and benefits associated with ME- informed HIV prevention interventions among PLWH and PWoH in the U.S. and there has been no large-scale engagement of key populations to determine how these risks and benefits are perceived. Furthermore, no previous studies focus on high HIV burden jurisdictions. Our overarching goal is to gauge the acceptability of ME approaches for HIV prevention research among key populations of PLWH and PWoH across the US, informed by well-characterized estimates of the risks and benefits. We will identify the facilitators and barriers that may impact those most affected by HIV-ME and develop guidance to improve acceptability of ME guided HIV prevention research. To do so we will address the following Specific Aims: 1) AIM 1 - Identify the perceived ethical, legal and social risks of molecular epidemiology for HIV prevention; 2) AIM 2 - Estimate the measurable scientific benefits and risks of molecular epidemiology; and 3) AIM 3 - Develop points to consider and guidance for designing and implementing research involving molecular epidemiology-informed approaches to HIV prevention.